Substituted tetrahydropyridine derivatives



United States Patent Claims. (Cl. 260-297) ABSTRACT OF THE DISCLOSURE The compounds are of the class of l,2,3,6-tetrahydropyridine derivatives substituted in 4-position a hydroxyalkyl group useful as analgesic and antitussive agents. An illustrative embodiment as a-ethyl-l-methyl-1,2,3,6-tetrahydro-4-pyridine ethanol.

CROSS-REFERENCE This is a continuation-in-part application of pending application Ser. No. 520,093, filed Jan. 12, 1966 which in turn is a continuation-in-part application of pending application Ser. No. 382,955 filed July 15, 1964.

DESCRIPTION OF INVENTION The present invention relates to compounds which may be characterized by the following Formula I Rz-CH-OH Hz? 2O wherein:

R represents alkyl with at most 4 carbon atoms or allyl, R represents alkyl with at most 4 carbon atoms or phenyl and their salts with inorganic and organic acids, all of which have valuable pharmacological properties. The instantly claimed compounds are particularly excellent antitussive agents; moreover, they have mild analgetic activity. There is no addiction liability either on administration as antitussives or as analgetics. Compounds of Formula I wherein R is methyl and R is alkyl of from 1 to 3 carbon atoms are preferred as they are particularly good nonaddicting antitussives.

In contrast to other analgetics, the presently claimed compounds have no parasympatholytic properties, rather they have a parasympathomimetic action. At the same time, they have a relatively low toxicity and are suitable, therefore, for the relief and removal of tussive irritation and also of pain of various origin.

The compounds of Formula I and their salts with inorganic and organic acids may be administered orally, rectally and parenterally.

The daily dosages of the free bases or of nontoxic salts thereof vary between 1 and 500 mg. for adult patients. Suitable dosage units such as drages (sugar coated tablets), tablets, suppositories or ampoules, preferably contain 1-200 mg. of an active substance according to the invention or of a non-toxic salt thereof.

By non-toxic salts of the bases usable according to the invention are meant salts with those acids the anions of which are pharmacologically acceptable in the usual dosages, i.e. those which have no toxic effects. It is also of advantage if the salts to be used crystallize Well and 3,399,206 Patented Aug. 27, 1968 are not or are only slightly hygroscopic. As non-toxic salts instead of the free bases, for example, the salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, B-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicyclic acid, phenyl acetic acid, mandelic acid and embonic acid can be used as active substances.

Furthermore, the present invention relates to novel compositions containing a compound of the above-mentioned formula for producing analgesic and antitussive effects in warm-blooded animals, especially mammals, when administered in therapeutic doses.

In the above described compounds R stands for alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl or allyl; R stands for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl or phenyl.

The production of compounds of general Formula I and their salts with inorganic and organic acids is characterized by partially reducing in that a compound of the general Formula II Rr-CO ill wherein R and R have the same meanings as defined above, and, if desired, converting the resulting compound Formula I to a salt with an inorganic or organic acid. The partial reduction is most simply performed by using reducing agents which do not attack, or at least do not seriously attack double bonds, e.g. alkali metal borohydrides in aqueous, aqueous/organic, particlarly aqueous/methanolic, or in alkanolic reaction media, as well as lithium aluminum hydride or diborane in an organic solvent containing at least one oxygen atom bound by an ether-type bond, such as diethyl ethyl, tetrahydrofuran or diethylene glycol dimethyl ether. The reduction temperature should be held between about 0 and the boiling temperature of the reaction medium used, but not be higher than, about The partial reduction can also be performed with catalytically activated hydrogen in organic or aqueous/organic medium. A suitable catalyst is, e.g. palladium-CaCO -lead acetate in ethanol partially deactivated in situ by the addition of quinoline (Lindlar catalyst, cf. Helv. Chim. Acta, 30, 1923 (1947)]The hydrogenation is performed, eg at room temperature under normal pressure and is interrupted after substantially the equimolar amount of hydrogen has been taken up.

The above-mentioned compounds of general Formula II can be produced from compounds of the general Formula III Rz-CO wherein Z represents a hydrogen atom or a low alkanoyl radical and R and R have the meanings given in Formula I, by splitting off Z-OH. Agents which split off water and are of the inorganic acid halide type such as chloride, or'organic acid anhydrides and halides such as acetanhydride, phthalic acid anhydride, acetyl chloride and acetyl bromide or other substances which, in themselves, have an acylating action'such as phenyl isocyanate can be used for this cleavage.

Compounds of the general Formula II in which the radical Z is hydrogen can be produced, in their turn, surprisingly easily by reacting a 4-piperidone of the general Formula IV HzC \CH2 Hz (5H;

N in (W) with a ketone of the general Formula V R -COCH (V) wherein R and R have the meanings given in general Formula I, the reaction being performed in the presence of a basic or acid substance in homogeneous or heterogeneous phase.

As basic condensing agents can be used, on the one hand, inorganic bases such as sodium hydroxide and organic bases such as piperidine, piperazine and, in anhydrous medium or in the presence of solvents, also alkali metal alcoholates, and on the other, basic ion exchangers, preferably those having quaternary ammonium groups such as Amberlite IRA 400 (0H or also more weakly basic ones such as Amberlite IR 4B, which can be used in batches or, optionally, in a continuous process. Depending on the solubility of the starting materials, water, an aqueous or an anhydrous low alkanol or another polar solvent can be used as reaction medium.

Examples of acid condensing agents are ammonium salts such as ammonium acetate, alone or combined with glacial acetic acid and, optionally an inert solvent, e.g. benzene, as well as acid ion exchangers, e.g. Amberlite IR 120 (H form) in water or an aqueous low alkanol as reaction medium.

In each of the above described modes of operation, condensation is preferably performed at room temperature to moderately raised temperature. At higher temperatures, water is generally split oii after the hydroxy compound has been formed, whereby the corresponding compound containing a cyclic double bond, i.e., a starting material falling under Formula II, is formed directly as main product. This is a sometimes advantageous modification of the above described process of producing compounds of Formula 11 via compounds of Formula IH. However, carrying out the process in two separate stages, namely, first by the actual aldol condensation and, secondly, the splitting off of water, is not always a less economical method of obtaining compounds of Formula II starting from compounds of the Formulae 1V and V, as it may lead to higher yields of pure starting material of the Formula II.

An acyl radical Z, e.g. an acetyl or propionyl radical, can easily be introduced by reacting compounds of the general Formula III containing a hydrogen atom as Z with the corresponding anhydride at room temperature or slightly raised temperature.

According to a second process, the compounds of general Formula I are produced by that a pyridinium compound of the general Formula VI Rr-CO 1 wherein X represents the hydroxyl ion, a monovalent anion or the normal equivalent of an anion, and R and R have the meanings given in Formula I, is partially reduced, i.e. until three times the molar amount of hydrogen has been taken up, and if desired, the compound obtained of general Formula I is converted into a salt with an inorganic or organic acid. Partial reduction is performed, for instance, with alkali metal borohydride, e.g. sodium or potassium borohydride, which can be used in the theoretical amount or in excess, in an aqueous or aqueous-organic medium e.g. aqueous-methanolic medium, at room temperature or moderately raised temperature.

The starting materials of the general Formula VI are obtained, e.g. from ketones of the general Formula VII wherein R has the meaning given in Formula I, in a known manner, e.g. by quaternization with a reactive ester of a hydroxy compound of the general Formula VIII R OH (VIII) wherein R has the meaning given in Formula I. This quaternization, e.g. with the corresponding halides or p-toluene sulphonic acid esters, can be performed in suitable organic solvents such as methanol, ethanol, ethyl acetate, dioxan, acetone or tetrahydrofuran.

Of the ketones of generalFormula VII, 1-(4'-pyridyl)- 2-prop'anone is known and other such ketones can be produced in an analogous way.

Examples of salts are the salts with. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, p-hydroxyethane sulphonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

The following examples further illustrate the performance of the processes according to the invention but are by no means the sole methods of performing same. The temperatures are given in degrees centigrade, and percentages are given by weight.

Example 1 17 g. of 1-(1-methyl-1,2,3,64tetrahydro-4'-pyridyl)- 2-butanone are dissolved in 170 ml. of methanol and, at 10 while stirring, a solution of 3.9 g. of sodium borohydride in 40 ml. of water and 4 'ml. of sodium hydroxide solution is slowly added. The mixture is then stirred at room temperature for another 2 hours and then evaporated in vacuo. Concentrated sodium hydroxide solution is added to the residue until the reaction is alkaline and it is then extracted with chloroform. The chloroform solution is dried, filtered, evaporated and the residue is distilled. The a-ethyl-1-methyl-l,2,3,6-tetrahydro-4-pyridine ethanol 1- 1'-methyll ',2',3 ,6-tetrahydro-4-pyridyl -2- butanol] boils at 81-86/0.02 ltorr. The distillate is dissolved in acetone and a solution of citric acid in acetone is added until the pH is 3. The citrate which precipitates is filtered oil and recrystallized from methanol/ether. It melts at 93-95 The following compounds are produced in an analogous manner:

a-l-dimethyl-1,2,3,6-tetrahydro-4-pyridine ethanol, B.P.

-79/-0.01 torr, citrate M.P. 1 07-1 10';

amethyl-l-propyl-1,2,3,6-tetrahydro-4 pyridine ethanol,

hydrochloride M.P. 154-155;

a-methyl-l-allyl-l,2,3,6-tetrahydro-4-pyridine ethanol,

hydrochloride M.P. 5254;

a-methyl- 1- (2'-phenylethy1) -1 ,2,3,6-tetrahydro-4-pyridine ethanol hydrochloride M.P. 183-186; a-propyl-l-methyl-1,2,3,6-tetrahydro-4-pyridine ethanol,

B.P. 69/0.0l torr, citrate M.P. lll7; a-phenyl-1-methyl-1,2,3,6-tetrahydro-4-pylridine ethanol,

citrate M.P. 84-86.

Example 2 1.5 g. of lithium aluminum hydride are dissolved in 25 ml. of abs. ether and the solution is refluxed for minutes. Then, at 10' While cooling, a solution of 4.8 g. of 1-(1'-methyl-l',2,3',6-tetrahydro-4-pyridy1l) 2 propanone in 15 ml. of abs. ether is slowly added dropwise within 15 minutes. The reaction mixture is stirred for another 3 hours at room temperature, then cooled at 10, 7 ml. of 70% methanol are added, a little Water is added and the whole is filtered. The filtrate is concentrated, the residue is dissolved in methylene chloride, the solution is dried and concentrated and the residue is distilled. The a,l-dirnethyl-l,2,3,6-tetrahydro-4-pyridine ethanol boils at 7577/ 0.01 torr, the citrate melts at 107-110".

Example 3 2.46 g. of 4-pyridyl acetone and 14.2 g. of methyl iodide in 30 ml. of methanol are refluxed for 3 hours. The solution is then evaporated in a rotary evaporator and the crude 4-pyridyl acetone metho-iodide which remains is worked up immediately.

3 g. of crude 4-pyridyl acetone metho-iodide are dissolved in 10 :ml. of methanol and a solution of 0.392 g. of sodium borohydride in 5 ml. of water and 0.5 ml. of 2 N sodium hydroxide solution is slowly added at 0. The whole is left to stand overnight at room temperature whereupon it is evaporated in a rotary evaporator, a small amount of concentrated sodium hydroxide solution is added and it is extracted three times with chloroform. It is dried, evaporated and distilled. The a,1-dimethyl-1,2,3,- 6-tetrahydro-4-pyridine ethanol boils at 7 0-80 under 0.01 torr. The distillate is dissolved in acetone and acetonic 6 citric acid solution is added until the pH is 3. The citrate which precipitates is filtered off and recrystallized from methanol/ether. It melts at 107110.

What is claimed is: 1. A compound selected from the class consisting of a l,2,3,-6-tetrahydropyridine derivative of the formula R2-OHOH (5H: H2O CH HgC C lia 1..

wherein:

R represents alkyl of at most 4 carbon atoms or allyl,

and

R represents alkyl of at most 4 carbon atoms or phenyl, and a therapeutically acceptable acid addition salt thereof 2. A compound as defined in claim 1, wherein R is methyl and R is alkyl of from 1 to 3 carbon atoms.

3. A compound as defined in claim '1, wherein R is methyl and R is ethyl.

4. A compound as defined in claim 1, wherein R and R are both methyl.

5. A compound as defined as claim 1, wherein R is methyl and R is propyl.

References Cited FOREIGN PATENTS 1,414,820 9/1965 France.

JOHN D. RANDOLPH, Primary Examiner.

A. L. ROTMAN, Assistant Examiner. 

